Hyperargininemia is considered to be the least common urea cycle disorder (UCD) encountered in clinical practice, with estimated incidence rates of 1 in 350,000-1,000,000 [1]. The pathogenesis stems from mutations in genes coding for the catalytic enzyme arginase that is necessary for the conversion of L-arginine to urea and ornithine [2] [3]. Hyperargininemia, like the majority of UCDs, is transferred through an autosomal recessive pattern of inheritance, but the clinical presentation differs from other UCDs in terms of the onset of symptoms and their severity [2] [4]. Namely, patients mainly start to develop first signs after infancy, in the period between ages 2 and 4, while severe hyperammonemia that is typical in other UCDs is often absent [2] [4]. Instead, a slowly progressive appearance of neurological manifestations is seen, starting with irritability, failure to thrive, feeding difficulties, and inability to reach appropriate developmental milestones [4] [5]. In the absence of proper therapy, more severe symptoms and signs are noted in a slowly progressive fashion - seizures (generalized tonic-clonic), progressive spastic diplegia, psychomotor and cognitive decline, as well as growth failure [1] [2] [4] [5]. In a subset of cases, episodes of vomiting and lethargy are observed [4]. Furthermore, liver diseases (cholestasis, liver failure, fibrosis, or even hepatocellular carcinoma) can be recognized in some cases of hyperargininemia [3] [6] [7].

• Cerebral Palsy

  Pearls & Alerts for Assessment Spastic diplegia may occur with cerebral palsy or arginase deficiency Children with a clinical presentation of cerebral palsy, particularly the spastic diplegic type, may have arginase deficiency. [medicalhomeportal.org]

  Hyperargininemia is one of the few treatable causes of pediatric spastic paraparesis, and can be confused with cerebral palsy. [pedneur.com]

• Poor Growth

  Without treatment, individuals will experience poor growth, stiff muscles, developmental delay, and intellectual disability. [myriad.com]

  Effects in infants can include: poor growth learning delays spasticity poor coordination and balance problems fussiness or illness when fed high protein food Episodes of illness caused by high levels of ammonia in the blood can sometimes occur but are [newbornscreening.info]

  Symptoms may include feeding problems, vomiting, poor growth, seizures, and stiff muscles with increased reflexes (spasticity ). [rarediseases.info.nih.gov]

• Movement Disorder

  Review Green Radboud University Medical Center, Nijmegen Phenotypes Argininemia, 207800 ARGININEMIA (ARGIN) ARG1 in Childhood onset dystonia or chorea or related movement disorder Version 1.4 Signed off v.1.2 on 25 Feb 2020 review Not set Sources Expert [panelapp.genomicsengland.co.uk]

  The deficiency often results in speech abnormalities, seizures, movement disorders, and an autistic-like behavioral phenotype. Our group has been actively developing a gene therapy approach to treat this condition. [lipshutzlabucla.com]

  When the above phenotype is seen, it is mandatory to screen for urea cycle disorders. [pediatricneurosciences.com]

  It can present with different symptoms than the first one such as movement disorders, psychiatric symptoms, confusion and abnormal behaviour. The anti-NMDA receptor encephalitis is treated differently to HSE. [encephalitis.info]

  Hyperammonemia can cause irritability, lethargy, refusal to eat, breathing difficulty, movement disorders, vomiting and, in severe cases, coma.[2] If arginase deficiency is undiagnosed or if the person with the disorder is unable to follow the strict [rarediseases.info.nih.gov]

• Short Stature

  The patient in this study was taken to our child health clinic at 3 years and 7 months old because of his short stature. [journals.lww.com]

  Untreated children may exhibit seizures, spasticity, short stature and intellectual disability. Most affected infants are now identified at birth through newborn screening. [rarediseases.org]

  Unlike other urea cycle defects, argininemia usually presents after 1 year of age with progressive spastic paraparesis, developmental delays, seizures that become progressively harder to control, and sometimes acquired microcephaly and short stature. [medicalhomeportal.org]

  Short stature in two patients, mongoloid eyes in one patient, hallux valgus in one patient, microcephaly in five patients, facial dysmorphism in four patients, and bony abnormalities in one patient (scoliosis) were the common associations [Figure 3]. [pediatricneurosciences.com]

  Clumsiness, failure to thrive, and short stature may be observed in early childhood; psychomotor deterioration may be seen from three months to four years of age. [invitae.com]

• Malaise

  The attacks usually begins with malaise often accompanied by headaches. A few hours later spiking fever ensues. An attack is accompanied by cervical lymphadenopathy, abdominal pain and arthralgias. Some patients have a rash, diarrhea and vomiting. [jessazh.be]

  Symptom Features  over 40C  preceding chills and malaise  affects up to 80%  various presentations (see below) Headache  nonspecific Enlarged lymph nodes in neck  characteristic  bilateral  painful  severe  diarrhoea and vomiting  peritonitis [slideshare.net]

  Signs and symptoms Patients with HSE may have a prodrome of malaise, fever, headache, and nausea, followed by acute or subacute onset of an encephalopathy whose symptoms include lethargy, confusion, and delirium. [emedicine.medscape.com]

• Failure to Thrive

  Instead, a slowly progressive appearance of neurological manifestations is seen, starting with irritability, failure to thrive, feeding difficulties, and inability to reach appropriate developmental milestones. [symptoma.com]

  Failure to thrive and dysmorphic features were also seen. Conclusion: Hyperargininemia commonly manifests as regression, failure to thrive, spasticity, seizures with or without microcephaly. [go.gale.com]

  Main features include failure to thrive, signs of hyperammonemia (anorexia, irritability, tachypnea, lethargy, vomiting), and additional neurologic signs (progressive spastic quadriplegia, seizures, mental retardation, hyperactivity). [accessanesthesiology.mhmedical.com]

  Later onset results in milder set of clinical features including vomiting, failure to thrive, irritability, behavioral problems, or psychomotor retardation. Mutations in the ARGININOSUCCINATE LYASE gene cause the disorder. [medvik.cz]

• Liver Fibrosis

  […] failure, or liver fibrosis. [agris.fao.org]

• Erythema

   Less common or rare skin presentations include:  Henoch-Schönlein purpura  erythema elevatum diutinum  petechiae (tiny bleeding spots or purpura)  erythema nodosum. o Oral and/or vaginal aphthous ulcers affect 50% of patients. [slideshare.net]

  […] aphthous stomatitis Recurrent canker sores 0011107 Urticaria Hives 0001025 Vasculitis Inflammation of blood vessel 0002633 5%-29% of people have these symptoms Acrocyanosis Persistent blue color of hands, feet, or parts of face 0001063 Ataxia 0001251 Erythema [rarediseases.info.nih.gov]

• Irritability

  Instead, a slowly progressive appearance of neurological manifestations is seen, starting with irritability, failure to thrive, feeding difficulties, and inability to reach appropriate developmental milestones. [symptoma.com]

  Infants may be irritable, vomit and exhibit feeding problems. They may be less alert when given cow's milk. Some infants may refuse to eat. Argininemia will affect the central nervous system. [thinkgenetic.com]

  Other symptoms that may present early in life include episodes of irritability, poor appetite, and vomiting. Severe episodes of hyperammonemia can occur but are infrequent. [rarediseasesnetwork.org]

  This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting. In some affected individuals, signs and symptoms of argininemia may be less severe, and may not appear until later in life. [wikidoc.org]

  Work with lung irritants: Those who work with chemicals, dust, smoke, or other lung irritants are at greater risk of hypercapnia. [medicalnewstoday.com]

• Encephalopathy

  Hyperargininemia Supergrp Primary hyperammonemia (Urea cycle disorders) [DS:H01398] Description Hyperargininemia is an autosomal recessive disorder caused by a defect in the arginase I enzyme resulting in high plasma arginine and ammonia levels, that develops encephalopathy [genome.jp]

  Hyperargininemic encephalopathy may present in adults and with atypical features. It should be kept in the differential diagnosis of metabolic encephalopathy in adults. [go.gale.com]

  Unlike other urea cycle disorders, this condition is not generally associated with a hyperammonemic encephalopathy in the neonatal period. [ncbi.nlm.nih.gov]

  Nota bene`: Urea cycle diseases are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. [humpath.com]

• Hyperactivity

  More Browse by letters A B C D E F G H I J K L M N O P Q R S T U V W X Y Z 0-9 Other dictionary words English hyped up hyper hyper kid hyperactive hyperactive behaviour hyperactive child hyperactive kids hyperactive thyroid hyperactivity hyperadrenalism [en.bab.la]

  Hyperactivity can be used to describe the increased action of a body function, such as… [tititudorancea.com]

  The major symptoms of AD are all progressive and include psychomotor retardation, spastic tetraplegia where the lower limbs are more affected than the upper, hyperactivity, growth failure and seizures. [themedicalbiochemistrypage.org]

  Main features include failure to thrive, signs of hyperammonemia (anorexia, irritability, tachypnea, lethargy, vomiting), and additional neurologic signs (progressive spastic quadriplegia, seizures, mental retardation, hyperactivity). [accessanesthesiology.mhmedical.com]

• Spastic Paraplegia

  In contrast to other urea cycle defects, arginase 1 deficiency usually does not cause catastrophic neonatal hyperammonemia but rather presents with progressive neurological symptoms including seizures and spastic paraplegia in the first years of life [agris.fao.org]

  Advances in the hereditary spastic paraplegias. Exp Neurol. 2003; 184: S106-S110 Blair M.A. Riddle M.E. Wells J.F. Breviu B.A. Hedera P. Infantile onset of hereditary spastic paraplegia poorly predicts the genotype. [pedneur.com]

  His spasticity severity score was 38/54 as assessed by the Spastic Paraplegia Rating Scale (SPRS) (6). Complex hereditary spastic paraplegias (HSPs) were diagnosed at first. [tp.amegroups.com]

• Chorea

  […] onset review BIALLELIC, autosomal or pseudoautosomal Sources Victorian Clinical Genetics Services Expert Review Green Radboud University Medical Center, Nijmegen Phenotypes Argininemia, 207800 ARGININEMIA (ARGIN) ARG1 in Childhood onset dystonia or chorea [panelapp.genomicsengland.co.uk]

  However morbidity remains high and survivors often have residual deficit such as chorea or epilepsy. A delay of 48 hours or more in starting acyclovir is associated with poor outcome. [orpha.net]

  Ataxia and chorea were present in one patient [Figure 4]. All children had poor growth and development [Figure 5] and [Figure 6]., Figure 3: Dysmorphic features. X-axis indicates clinical features. [pediatricneurosciences.com]

Because of the rather rare occurrence of hyperargininemia in clinical practice, the diagnosis might be difficult to attain without adequate clinical suspicion. For this reason, a thorough clinical investigation comprised of a meticulously obtained patient history and a detailed physical examination is of critical importance. The course and progression of symptoms should be assessed with the parents, whereas signs of upper motor neuron damage (hyperreflexia, spasticity) are hallmarks of hyperargininemia on a neurological exam [4]. Furthermore, ataxia, toe walking, and cognitive impairment may be noted [4]. Magnetic resonance imaging (MRI) of the endocranium is a useful procedure in the evaluation of patients suffering from hyperargininemia, showing both cerebral and cerebellar atrophy. Microcephaly could be present in some cases. Electroencephalography (EEG) is also an important component of the diagnostic workup [4], but in order to confirm hyperargininemia, biochemical or genetic testing is necessary. The measured activity of arginase will reveal abnormally low values [4] [5].

• Hepatocellular Carcinoma

  Some patients have developed hepatocellular carcinoma. A usually mild or moderate hyperammonemia may occur at any age. The pathogenesis of arginase I deficiency is yet not fully understood. [agris.fao.org]

  Furthermore, liver diseases (cholestasis, liver failure, fibrosis, or even hepatocellular carcinoma) can be recognized in some cases of hyperargininemia. [symptoma.com]

Urinary orotic acid concentration Red blood cell arginase enzyme activity (measurement) Treatment[edit] The treatment for infants (individuals) with argininemia is the following, including medications:[3] Protein intake limited Sodium benzoate Sodium [en.wikipedia.org]

In case 2, hyperargininemia was identified through newborn screening and treatment was started when patient was 21 days old. Cholestasis was only identified in the patient's further evaluation and it resolved 2 weeks into treatment. [ncbi.nlm.nih.gov]

Some infants who were diagnosed and treatment from birth have remained symptom-free through a special diet and medication. This will also stop symptoms from getting worse if they have already begun. [thinkgenetic.com]

Once the diagnosis is confirmed, treatment options consist of protein restriction and using alternate techniques to remove nitrogenous wastes as well as supplementing essential amino acids.[7],[8] With the aforementioned treatment, the arginine levels [pediatricneurosciences.com]

European Journal of Human Genetics 6(SUPPL 1): 48, 1998 Diagnosis and treatment of argininemia characteristics of arginase ec 3531 in human erythrocytes and tissues. 1984 Chemically defined diet in the treatment of kwashiorkor. [eurekamag.com]

The prognosis of Arginase Deficiency Disorder is generally good, so long as the necessary dietary restrictions are adhered to and proper medication is taken before symptom onset There are no preventive measures available for this disorder, as it is caused [dovemed.com]

Causes Differentiating Argininemia from Other Diseases Epidemiology and Demographics Risk Factors Screening Natural History, Complications, and Prognosis Diagnosis Argininemia usually becomes evident by about the age of 3. [wikidoc.org]

Prognosis HIDS has a good prognosis. Life expectancy is not shortened except for in rare cases where severe infections or renal amyloidosis occur. The documents contained in this web site are presented for information purposes only. [orpha.net]

In case 1, diagnosis was established at 2 months of age upon investigation of the etiology of cholestatic injury pattern and hepatosplenomegaly, and treatment was then initiated at when the patient was 3 months old. [ncbi.nlm.nih.gov]

Etiology argininemia is caused by mutation in the gene encoding liver arginase (ARG1) (MIM.608313). Nota bene`: Urea cycle diseases are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. [humpath.com]

Qualificadores Permitidos Inglês: BL blood CF cerebrospinal fluid CI chemically induced CL classification CO complications DI diagnosis DG diagnostic imaging DH diet therapy DT drug therapy EC economics EM embryology EN enzymology EP epidemiology EH ethnology ET etiology [decs.bvsalud.org]

Qualifiers English: BL blood CF cerebrospinal fluid CI chemically induced CL classification CO complications DI diagnosis DG diagnostic imaging DH diet therapy DT drug therapy EC economics EM embryology EN enzymology EP epidemiology EH ethnology ET etiology [decs.bvs.br]

Regarding etiology, NHF is differently classified in the literature, without consensus3,4,6,7. [scielo.br]

Retrieved 20 November 2016.update 2014 ^ a b c d "Arginase Deficiency: Background, Pathophysiology, Epidemiology". eMedicine. 15 April 2016. Retrieved 28 November 2016. ^ a b c Reference, Genetics Home. "ARG1 gene". Genetics Home Reference. [en.wikipedia.org]

Histórica Inglês: 2000 Qualificadores Permitidos Inglês: BL blood CF cerebrospinal fluid CI chemically induced CL classification CO complications DI diagnosis DG diagnostic imaging DH diet therapy DT drug therapy EC economics EM embryology EN enzymology EP epidemiology [decs.bvsalud.org]

Note English: 2000 Allowable Qualifiers English: BL blood CF cerebrospinal fluid CI chemically induced CL classification CO complications DI diagnosis DG diagnostic imaging DH diet therapy DT drug therapy EC economics EM embryology EN enzymology EP epidemiology [decs.bvs.br]

Causes Differentiating Argininemia from Other Diseases Epidemiology and Demographics Risk Factors Screening Natural History, Complications, and Prognosis Diagnosis Argininemia usually becomes evident by about the age of 3. [wikidoc.org]

[…] novel R21X mutation in the liver-type arginase gene (ARG1) in four Portuguese patients with argininemia. 53 62 5 Cardoso ML...Rocha J 10502833 1999 13 Molecular genetic study of human arginase deficiency. 53 62 5 Grody WW...Leonard JV 1598908 1992 14 Epidemiology [malacards.org]

However, the accumulation of L-arginine and the resulting abnormalities in the metabolism of guanidine compounds and nitric oxide have been proposed to play a major pathophysiological role. [agris.fao.org]

Retrieved 20 November 2016.update 2014 ^ a b c d "Arginase Deficiency: Background, Pathophysiology, Epidemiology". eMedicine. 15 April 2016. Retrieved 28 November 2016. ^ a b c Reference, Genetics Home. "ARG1 gene". Genetics Home Reference. [en.wikipedia.org]

However, the accumulation of l-arginine and the resulting abnormalities in the metabolism of guanidine compounds and nitric oxide have been proposed to play a major pathophysiological role. [scinapse.io]

They usually spontaneously adopt a low-protein diet to prevent hyperammonemia. [medicalhomeportal.org]

Perioperative nutrition should aim for high carbohydrate intake and low protein intake to prevent arginine load. To prevent a catabolic state, avoid longer fasting periods and/or cover them with dextrose-containing intravenous solutions. [accessanesthesiology.mhmedical.com]

In a patient with hyperargininemia, oral administration of sodium benzoate or phenylacetic acid together with an essential amino acid mixture was used to prevent hyperammonemia and to decrease plasma and CSF concentrations of arginine. [ncbi.nlm.nih.gov]

Excreting the excess nitrogen prevents it from accumulating in the form of ammonia, which is toxic. [ghr.nlm.nih.gov]

1. Maramattom BV, Raja R, Balagopal A. Late onset arginase deficiency presenting with encephalopathy and midbrain hyperintensity. Ann Indian Acad Neurol. 2016;19(3):392-394.
2. Crombez EA, Cederbaum SD. Hyperargininemia due to liver arginase deficiency. Mol Genet Metab. 2005;84(3):243-251.
3. Schlune A, Vom Dahl S, Häussinger D, Ensenauer R, Mayatepek E. Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature. Amino Acids. 2015;47(9):1751-1762.
4. Scaglia F, Lee B. Clinical, Biochemical, and Molecular Spectrum of Hyperargininemia Due to Arginase I Deficiency. Am J Med Genet C Semin Med Genet. 2006;0(2):113-120.
5. Hewson S, Clarke JT, Cederbaum S. Prenatal diagnosis for arginase deficiency: a case study. J Inherit Metab Dis. 2003;26:607–610.
6. Oldham MS, vanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion Tensor Imaging in Arginase Deficiency Reveals Damage to Corticospinal Tracts. Pediatr Neurol. 2010;42(1):49-52.
7. Cederbaum SD, Yu H, Grody WW, Kern RM, Yoo P, Iyer RK. Arginases I and II: do their functions overlap? Mol Genet Metab. 2004;81(Suppl 1):S38–S44.